BRPI0212922B1 - PHARMACEUTICAL COMPOSITION IN THE FORM OF A DISPERSABLE TABLET UNDERSTANDING A SOLID 40-O- (2-HYDROXIETIL) DISPOSITION, ITS PROCESS FOR PREPARING AND USING DIET COMPOSITION - Google Patents

Abstract

"pharmaceutical compositions". A pharmaceutical composition comprising a solid macrolide dispersion, a disintegrant and colloidal silicon dioxide, wherein the composition comprises 1 to 5% colloidal silicon dioxide by weight.

Description

(54) Title: PHARMACEUTICAL COMPOSITION IN THE FORM OF A DISPERSABLE TABLET UNDERSTANDING A SOLID DISPERSION OF 40-O- (2-HYDROXYETHYL) -RAPAMICIN, ITS PROCESS OF PREPARING AND USING THIS COMPOSITION (51) Int.CI .: A61K 9 / 20; A61K 31/435; A61K 31/445 (30) Unionist Priority: 28/09/2001 GB 01 23400.4 (73) Holder (s): NOVARTIS AG (72) Inventor (s): BARBARA HAEBERLIN; ANDRÉA KRAMER; SILVIA HEUERDING

DESCRIPTION REPORT OF THE PATENT FOR PHARMACEUTICAL COMPOSITION IN THE FORM OF A DISPERSABLE TABLET UNDERSTANDING A SOLID DISPERSION OF 40-0- (2HYDROXYETHYL) -RAPAMICIN, ITS PREPARATION AND PROCESS

USE OF SUCH COMPOSITION.

The present invention relates to new oral pharmaceutical compositions comprising a macrolide, for example, rapamycin or a derivative thereof or an ascomycin in a solid dispersion.

The term macrolide as used herein, refers to a macrocyclic lactone 10, for example, a compound having a 12-membered lactone ring, or greater. Of particular interest are lactam macrolides, that is, macrocyclic compounds having a lactam (amide) bond in the macrocyclic, in addition to a lactone (ester) bond, for example lactam macrolides produced by microorganisms of the genus Streptomyces such as, rapamycin, ascomycin and FK-506, and their various derivatives and analogs. Such lactam macrolides have been shown to have interesting pharmaceutical properties, specifically immunosuppressive and anti-inflammatory properties.

Rapamycin is an immunosuppressive lactam macrolide that is produced by Streptomyces hygroscopicus. The structure of rapamycin is provided in Kesseler, H., et al., 1993; Helv. Chim. Minutes; 76: 117. See, for example, McAlpine, J.B. et al., J. Antibiotics (1991) 44: 688; Schreiber, S.L., et al., J. Am. Chem. Soc. (1991) 113: 7433; US patent number 3,929,992. Rapamycin is an extremely potent immunosuppressant and has also been shown to have antitumor and antifungal activity. Its usefulness as a pharmaceutical composition, however, is restricted by its very low and variable bioavailability. In addition, rapamycin is highly insoluble in an aqueous medium, for example water, making it difficult to formulate galenic compositions. Various rapamycin derivatives are known. Certain 16-0 substituted rapamycin derivatives are disclosed in WO 94/02136, the contents of which are incorporated herein by reference. The 40-0 substituted rapamycin derivatives are described, for example, in US 5,258,389 and WO 94/09010 (rapamycin derivatives O-aryl and Oalkyl); WO 92/05179 (carboxylic acid esters), US 5,118,677 (amide esters), US 5,118,678 (carbamates), US 5,100,883 (fluorinated esters),

yes

US 5,151,413 (acetals), US 5,120,842 (silyl ethers), WO 93/11130 (methylene rapamycin and derivatives), WO 94/02136 (methoxy derivatives), WO 94/02385 and WO 95/14023 ( alkenyl derivatives) all of which are incorporated herein by reference. Derivatives of substituted rapamycin or 32O-dihydro are described, for example, in US 5,256,790, incorporated herein by reference.

Additional rapamycin derivatives are described in PCT application EP96 / 02441, for example, 32-deoxorapamycin is described in Example 1 and 16-pent-2-inyloxy-32 (S) -dihydrorrapamycin is described in Examples 2 and 3. The content PCT application EP96 / 02441 is hereby incorporated by reference.

Rapamycin and its structurally related derivatives are collectively referred to as rapamycin and rapamycin derivatives.

The class of ascomycin, of which FK-506 and ascomycin are the best known elements, comprises another class of lactam macrolides, many of which have potent immunosuppressive and anti-inflammatory activity. FK506 is a macrolide immunosuppressant that is produced lactam by Streptomyces tsukubaensis No 9993. The structure of FK506 is given in the appendix to the Merck Index, 11th edition (1989) as item A5. Ascomycin is described, for example, in US patent 3,244,592. Many derivatives of ascomycin and FK-506 have been synthesized, including halogenated derivatives, such as, 33-epi-chloro-33-deoxy-ascomycin described in EP 427,680. Ascomycin, FK-506 and their structurally similar analogs and derivatives are collectively called ascomycin and ascomycin derivatives.

In oral administration to humans, solid rapamycin or rampacin derivatives may not be absorbed to any significant extent in the bloodstream. PCT application WO 97/03654, the content of which is incorporated herein by reference, describes pharmaceutical compositions in the form of a solid dispersion comprising a macrolide, for example, a rapamycin, ascomycin or a derivative thereof, and a medium vehicle. These compositions provide improved bioavailability of the drug substance, are convenient to administer and are stable.

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However, for certain groups of patients, oral administration of drugs in the form of solid tablets is both undesirable and impractical. Specifically, children and elderly patients may be unable to swallow such pills properly. For these patients, it is typically more desirable to provide a tablet that can first be dispersed in an ingestible liquid, prior to consumption by the patient.

For administration to children and elderly patients, it would be highly desirable to provide a tablet that disperses rapidly in an ingestible liquid, such as water. A problem with prior art macrolide formulations is that, since they do not necessarily disperse rapidly in aqueous solutions, it can be inconvenient and time consuming to prepare a sufficiently dispersed liquid formulation prior to administration to the patient. A specific difficulty in formulating a solid macrolide dispersion composition in the form of a dispersible tablet is the high amount of vehicle used in the solid dispersion compositions, acting as a binder in the tablet formulations.

It is known that a faster disintegrating tablet can be produced by using a lower compaction force during the tablet manufacturing process. However, this typically results in a tablet that has inferior mechanical properties. Specifically, weakly pressed tablets show insufficient stiffness and are liable to crumble, chip or disintegrate before this is desired (that is, during packaging, transit, storage or at any time before adding the tablet to the ingestible liquid for consumption).

The present invention claims to provide a pharmaceutical composition that alleviates the problems of the prior art compositions. Accordingly, the present invention provides a pharmaceutical composition comprising a dispersion of macrolide solid, a disintegrant and colloidal silicon dioxide, where the composition comprises 1 to 5% colloidal silicon dioxide by weight.

The present invention is based on the surprising finding that a specific quick dispersion composition comprising a dispersion of macrolide solid can be provided by using colloidal silicon dioxide to promote disintegration. Colloidal silicon dioxide is known in the prior art primarily as a lubricant or flow regulating agent in pharmaceutical compositions. Where used for such purposes, silicon dioxide typically comprises about 0.5% by weight of the composition. According to the present invention, it has been found that the inclusion of 1 to 5% by weight of colloidal silicon dioxide is specifically effective in promoting the disintegration of a solid macrolide dispersion in the aqueous solution, when combined with another disintegrant.

In addition, the compositions of the present invention show high stability and physical integrity, for example, during storage, handling, packaging and the like, without limiting the disintegrating performance of the composition. The inclusion of colloidal silicon dioxide in the appropriate amount is additionally advantageous because it results in a composition that, when pressed into a tablet, has improved mechanical properties. Specifically, tablets formed from the compositions according to the present invention have a surprising combination of rapid disintegration in aqueous solutions with mechanical stability. For a given level of stiffness, the inclusion of silicon dioxide results in tablets having a faster disintegration rate. Alternatively, for a given disintegration rate, tablets containing silicon dioxide according to the present invention are more rigid than tablets that do not contain silicon dioxide.

The compositions of the present invention comprise one or more disintegrants. Examples of disintegrants include cross-linked polyvinylpyrrolidone, for example, as commercially available as Crospovidone® or Polypasdone® (Handbook of Excipients, pages 143-144) available from the ISP; sodium starch glycolate available from Generichem; and croscarmellose sodium, for example, as commercially available as Ac-di-sol® from FMC Corporation. Preferably, the disintegrant ···· · ····· · • · · · ·· · · · comprises cross-linked polyvinylpyrrolidone.

Crospovidone® is preferably included in the composition of this invention in an amount of up to about 50% by weight, for example, to 30% by weight, more preferably in an amount of about 20%, all weights based on the total weight of the composition .

The compositions of the present invention comprise 1 to 5% by weight of colloidal silicon dioxide, in addition to a disintegrant as defined above. Colloidal silicon dioxide can be obtained commercially available as Aerosil®. Colloidal silicon dioxide is included in the composition of this invention in an amount of 1 to 5% of the total weight of the composition, preferably in an amount of 2 to 5% of the total weight of the composition.

More preferably, the composition comprises 2 to 4% and even more preferably 2.5 to 3.5% of the colloidal silicon dioxide based on the total weight of the composition. More preferably, the composition comprises about 3% of colloidal silicon dioxide by weight.

Preferably, a mixture of colloidal silicon dioxide and cross-linked polyvinylpyrrolidone can be used, for example, in a ratio of 1: 1 (such as 1: 3) to 1:50 (such as 1:10).

The macrolide used in the solid dispersion of this invention can be rapamycin or any derivative thereof, for example, a substituted O derivative, in which the hydroxyl group on the rapamycin cyclohexyl ring is replaced by -OR-i where Ri is hydroxyalkyl, hydroxyalkoxyalkyl, acylaminoalkyl or aminoalkyl; for example, as described in WO 94/09010, for example, 40-O- (2-hydroxyethyl) -rapamycin, 40-O- (3-hydroxypropyl) rapamycin, 40-O- [2- (2-hydroxyethoxy) ethyl ] -rapamycin and 40-O- (2-acetaminoethyl) rapamycin. The rapamycin derivative can be a 26 or 28 substituted derivative. The rapamycin derivative can be an epimer of a derivative mentioned above, specifically an epimer of a substituted derivative at position 40, 28 or 26, and can be optional and additionally hydrogenated. , for example, as disclosed in WO 95/14023 and 99/15530, for example ABT578, or it can be a rogue as disclosed, for example, in WO 98/02441 and WO 01/14387, for example, AP23573.

Preferred rapamycin derivatives for use in this invention include rapamycin, 40-O- (2-hydroxy) ethyl rapamycin, 32-deoxorapamycin and 16-pent-2-ynyloxy-32 (S) -dihidrorrapamycin. A more preferred compound is 40-O- (2-hydroxy) ethyl rapamycin.

The numbering of the rapamycin derivatives as used here, refers to the structure disclosed as Formula A on page 4 of PCT WO 96/13273, incorporated herein by reference.

Examples of compounds of the class of ascomycin are those mentioned above, for example, FK-506, ascomycin and other naturally occurring compounds or synthetic analogs thereof.

A preferred compound of the ascomycin class is disclosed in EP 427,680, Example 66a, also known as 33-epi-chloro-33-deoxiascomycin. Other preferred compounds are disclosed in EP 465,426 and EP 569,337 (Example 71). Specifically preferred is 33-epi-chloro-33 deoxy-ascomycin.

The macrolide (for example, rapamycin or a derivative thereof, such as 40-O- (2-hydroxyethyl) rapamycin or an ascomycin, such as 33-epi-chloro-33-deoxy-ascomycin or FK-506) is found if preferably present in the composition in an amount of about 0.01 to about 30%, more preferably 0.1 to 20% by weight, based on the total weight of the composition. Specifically, a rapamycin derivative, for example, 40-O- (2-hydroxy) ethyl rapamycin, can be present in the composition in an amount of 0.1% by weight.

The macrolide used in this invention, can be in crystalline or amorphous form, before the formation of the solid dispersion. An advantage, therefore, of this invention, is that the macrolide need not be crystalline. Thus, the macrolide can be used directly in combination, for example, with a solvent and does not need to be isolated in advance. Another advantage of the invention is that the dissolution rates of the solid dispersion are higher than the dissolution rates found for a crystalline macrolide or an amorphous macrolide in a simple mixture.

The preferred medium for the preparation of the solid dispersion

It comprises a vehicle, for example, a water-soluble polymer, for example, one or a mixture of the following polymers can be used:

- hydroxypropylmethylcellulose (HPMC). Good results can be obtained using HPMC with a low apparent viscosity, for example, below 100 cps as measured at 20 ° C to 2% by weight of the aqueous solution, for example, below 50 cps, preferably below 20 cps, for example example, HPMC 3 cps. HPMC is well known and described, for example, in the Handbook of Pharmaceutical Excipients, pub. Pharmaceutical Society of Great Britain and American Pharmaceutical Association, 1994, pages 229 to 232, the content of which is incorporated herein by reference. HPMC, including HPMC 3 cps, is commercially available under the trademark Pharmacoat® 603 from Shinetsu company:

- Hydroxypropylmethylcellulose phthalate (HPMCP), for example, as commercially available as HPMCP HP50 or HPMCP HP55;

- polyvinylpyrrolidone (PVP), for example, PVP K30 or PVP K12. PVP is commercially available, for example, as Povidone® (Handbook of Pharmaceutical Excipients, pages 392-399) from BASF Company. A PVP having an average molecular weight between about 8,000 and about 50,000 Daltons is preferred, for example, PVP K30;

- poly (meth) acrylates, for example, a copolymer that is resistant to gastric juice and soluble in intestinal juices, for example, a copolymer formed from monomers selected from the group consisting of methacrylic acid, methacrylic acid esters, acrylic acid and esters of acrylic acid, such as those known and commercially available as Eudragit® from Rohm Pharma GmbH. An especially preferable polymer is copolymer 1: 1 or 1: 2, formed from monomers selected from the group consisting of methacrylic acid and lower alkyl esters of acid methacrylic, such as copolymer 1: 1 or 1: 2, formed from methacrylic acid and methyl methacrylate. Copolymers 1: 1 are available as Eudragit® L, copolymers 1: 2 are available as Eudragit® S. A specifically preferred polymer is copolymer 1: 1 of me8 acid

tacrylic and acrylic acid ethyl ester, commercially available as Eudragit® L 100-55;

- Hydroxypropylcellulose (HPC) or a derivative thereof. Examples of HPC derivatives include those having low dynamic viscosity in the aqueous medium, for example, water, for example, below about 400 cps, for example, below 150 cps, as measured in a 2% aqueous solution at 25 ° Ç. Preferred HPC derivatives have a lower degree of substitution and an average molecular weight below about 200,000 Daltons, for example, between 50,000 and 150,000 Daltons. Examples of commercially available HPC include Klucel® LF, Klucel® EF and Klucel®JF from Aqualon company and Nisso® HPC-L available from Nippon Soda Ltd;

- Polyethylene glycol (PEG). Examples include PEGs having an average molecular weight between 1,000 and 9,000 Daltons, for example, between about 1,800 and 7,000, for example PEG 2000, PEG 4000 or PEG 6000 (Handbook of Pharmaceutical Excipients, pages 355-361);

- Saturated polyglycosylated glyceride, available for example as Gelucire®, for example, Gelucire® 44/14, 53/10, 50/13, 42/12 or 35/10 from Gattefossé Company; or

- Cyclodextrin, for example, β-cyclodextrin or an acyclodextrin. Examples of suitable β-cyclodextrin include methyl-βcyclodextrin; dimethyl ^ -cyclodextrin; hydroxypropyl? -cyclodextrin; glycosyl-βcyclodextrin; maltosyl ^ -cyclodextrin; sulpho-cyclodextrin; β-cyclodextrin sulfo-alkylethers, for example, sulfo-C-M alkyl ethers. Examples of acyclodextrins include glycosyl-a-cyclodextrin and maltosyl-a-cyclodextrin.

The medium vehicle of the solid dispersion is present in an amount of, for example, 0.1 to 99.99% by weight, for example, 0.1 to 99.9%, for example 1 to 95%, for example 5 to 95%, for example 10 to 90% based on the total weight of the solid dispersion.

In one embodiment of this invention, the solid dispersion composition comprises 2% by weight of rapamycin or a derivative thereof, for example, 40-O- (2-hydroxy) ethyl rapamycin and 80% by weight of

HPMC 3 cps.

The means vehicle for preparing the solid dispersion may additionally comprise one or a combination of soluble or water-insoluble sugar, or other acceptable carrier or filler, such as sucrose, lactose, amylose, dextrose, mannitol, inositol and the like, preferably lactose or microcrystalline cellulose, for example, commercially available as Avicel®, Pharmacel®, Emcocel® and Vivapur®, from FMC Corporation (Handbook of Pharmaceutical Excipients, pages 84-87). Preferably, lactose can be used.

A filler, if present, can generally be present in an amount of up to about 50% by weight, for example, from about 0.01 to about 50%, for example, from about 0.5 to about 40 %, preferably from about 5 to about 35%, specifically about 20%, based on the total weight of the solid dispersion.

The medium vehicle may additionally comprise one or more surfactants, for example, a nonionic or amphoteric surfactant. Examples of suitable surfactants include:

- polyoxyethylene-polyoxypropylene copolymers and block copolymers, commercially available as Pluronic or Poloxamer, e.g., as described in H.Fiedler, Lexikon der Hifsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, Editio Cantor Verlag Aulendorf, Aulendorf, 4th revised and expanded edition (1996), the content of which is incorporated here as a reference. A polyoxyethylene polyoxypropylene block copolymer is Poloxamer® 188, commercially available from BASF company;

- ethoxylated cholesterins, commercially available as Solulan®, for example, Solulan® C24 from Amerchol company:

- vitamin derivatives, for example, vitamin E derivatives, such as tocopherol polyethylene glycol succinate (TPGS), available from Eastman company:

- sodium dodecyl sulphate or sodium lauryl sulphate;

- a bile acid or salt thereof, for example, cholic acid, glycolic acid or a salt, for example, sodium cholate; or

- lecithin, for example, soy phospholipid, for example, commercially available as Lipoid® S75 from Lipoid; or by egg phospholipid, for example, commercially available as Nattermann's Phospholipon®90.

If present, the surfactant (s) may generally be present in an amount of about 0.01% to about 30% by weight, for example, 1 to 20% in weight. weight, for example, 1 to 15%, all weights based on the weight of the solid dispersion. Depositors achieved good results using solid dispersions free of surfactant.

In another embodiment, the carrier vehicle for preparing the solid dispersion may comprise additional additives or ingredients, for example, an antioxidant and / or stabilizer, for example, in an amount of about 5% by weight, for example, about 0.05 to 5% by weight, for example, 0.05 to 1%, specifically about 0.2%, all weights based on the total weight of the solid dispersion composition. Examples of antioxidants include butylated hydroxytoluene (BHT), butyl anisol hydroxy (BHA), DL-atocopherol, propyl gallate, ascorbyl palmitate and fumaric acid. Preferably, butylated hydroxytoluene can be used. Malonic acid can be an appropriate stabilizer.

The rapamycin 40-O- (2-hydroxy) ethyl can be specially mixed with a stabilizer, for example, butylated hydroxytoluene, for example, in a ratio of 5: 1 to 20: 1.

The carrier medium may additionally include antimicrobial agents, enzyme inhibitors and preservative agents.

In another aspect, the present invention relates to a process for producing a macrolide-containing pharmaceutical composition, comprising preparing a solid macrolide dispersion and mixing the solid macrolide dispersion with a disintegrant and colloidal silicon dioxide to form the pharmaceutical composition.

In the above process, the solid macrolide dispersion is prepared first. The term solid dispersion as used here means a preparation in which the macrolide is amorphous or substantially

amorphous and is dispersed in a medium vehicle. For example, the solid dispersion can be co-precipitated or co-evaporated from the macrolide with the medium vehicle. The solid dispersion can be a composition that is adapted for further processing in a manageable formulation.

A - In one embodiment, the solid dispersion can be obtained by dissolving or suspending the macrolide and medium vehicle, for example, comprising a water-soluble polymer, a filler and an antioxidant, in a solvent or solvent mixture. The solvent may be a single solvent or mixture of solvents and the order of dissolution and suspension of the macrolide with the medium vehicle in the solvent may vary. The solvents suitable for use in the preparation of the solid dispersion can be organic solvents, such as, alcohol, for example, methanol, ethanol or isopropanol; an ester, for example, ethyl acetate; an ether, for example diethyl ether; a ketone, for example, acetone; or a halogenated hydrocarbon, for example, dichloroethane. Preferably, an ethanol / acetone solvent mixture having an ethanol: acetone weight ratio between about 1:10 to about 10: 1, for example, 1: 5 to 5: 1; can be used. Typically, the macrolide and medium vehicle are present in a weight to solvent ratio of 1: 0.1 to 1:20. The solvent can be evaporated and the macrolide co-precipitated with the carrier medium.

B - In another embodiment, the solid dispersion can be prepared by melting the medium vehicle to form a melt, and combining the melt with the macrolide, for example, by stirring, optionally in the presence of a solvent or solvent mixture as described here. The resulting mixture can be granulated with a filler, for example, lactose or mannitol.

C - In another embodiment, the solid dispersion can be prepared by dissolving or suspending the macrolide and carrier medium in a solvent or mixture of solvent as described above, and granulating the resulting solution / dispersion with a filler, for example, lactose.

D - The solid dispersion can be prepared by spray drying techniques, as described, for example, in Theory and Prac • tice of Industrial Pharmacy, Lachmann et al., 1986. A solution / dispersion of the macrolide and medium vehicle in a solvent or solvent mixture as described above, is dispersed through a nozzle in a chamber maintained at, for example, 20 to 80 ° C and a spray pressure of, for example, 300 kPa (3 bar). The solvent is evaporated through the nozzle and finely dispersed particles are collected.

E - In a further embodiment, the solid dispersion can be prepared by granulation by spraying the solution / dispersion of the macrolide and carrier medium in a solvent or solvent mixture, as described above in a filler, for example, lactose or microcrystalline cellulose, or a mixture of them in a fluid bed.

According to the present invention, the solid dispersion containing macrolide as described above is further processed into the pharmaceutical composition in the form of a dispersible tablet. The dispersible tablet preferably has a disintegration time of 3 minutes or less.

In an alternative aspect of this invention, the solid dispersion composition, as described above, can be further processed into a rapidly disintegrating powder or granules that can be filled into sachets or gelatin capsules.

The residues resulting from each of the processes A to B described above can be sieved and ground into particles, for example, having an average particle size of less than 0.9 mm, for example, less than about 0.8 mm, for example. example, less than about 350 microns. Preferably, the particle size is at least about 5 microns, for example, 200 to 300 microns.

The solid (ground) dispersion can be combined with colloidal silicon dioxide, one or more disintegrants, such as Crospovidona®, and other excipients, such as filler, for example, lactose, and mixed, sieved and combined with a lubricant , for example, magnesium stearate, mixed and, for example, pressed to obtain a dispersible tablet, or loaded in sachets or gelatin capsules.

One or more lubricants, such as magnesium stearate, can be additionally included in the composition of this invention. Magnesium stearate can be included in an amount of 0.5 to 2% by weight, preferably about 0.5% all by weight, based on the total weight of the composition.

In a specifically preferred embodiment, the pharmaceutical composition further comprises a lubricant and a filler.

It may be advantageous to include one or more sweetening or flavoring agents in the compositions of this invention, for example, in an amount of about 2.5 to 5% by weight, based on the total weight of the composition.

In another embodiment of this invention, a water-soluble, or water-insoluble sugar, or other acceptable filler, such as lactose sucrose, or microcrystalline cellulose (for example, as available as Avicel®, from FMC Corporation) may be included in the compositions of this invention. Preferably, lactose, specifically anhydrous lactose, can be used, for example, in an amount of up to about 90% by weight, for example, 20 to 80% by weight, preferably about 50 to about 72%, all weights with based on the total weight of the composition.

The rapid disintegration compositions of this invention can be administered in any convenient form, for example, in tablet, capsule, granule or powder form, for example, in a sachet. Preferably, the formulation is in the form of a tablet. Considering that hereinafter the compositions of the invention will be described with specific reference to tablets, other types of dosage forms can be produced and are included within the scope of this invention.

Tablets can be produced from the compositions of the present invention using any appropriate apparatus or procedure. Typically, a tablet press is used to press the compositions. Variable amounts of the compositions can be pressed in order to produce tablets of different weights. In preferred embodiments, 50 to 500 mg of the composition are pressed in each batch14

«· Ί * · · ···· ·· ·· ··» ·· «« »· 4» ··· * • · · · ·· · · press. More preferably, the tablets are produced having a weight of about 100 mg or about 250 mg.

The force used to press the present compositions can vary, in order to vary the stiffness and disintegration time of the resulting tablets. The use of a higher compression force results in a more rigid tablet and a longer disintegration time. For a dispersible tablet, it is important that the disintegration time is short enough, so that the tablet can be conveniently dispersed in the aqueous solution, before consumption. Therefore, it is necessary to select an appropriate compression force in order to obtain the desired disintegration time.

However, it is also important that the tablets have a sufficient degree of mechanical strength. The present compositions are advantageous because of a given compressive strength, the resulting tablets disintegrate more quickly in an aqueous solution than the prior art tablets. Even so, the tablets of the present invention maintain a sufficient degree of rigidity. In order to obtain a dispersible tablet having a sufficiently short disintegration time, using the formulations of the prior art, a very low compression force would be required. This would produce a tablet having inadequate mechanical and rigidity properties.

It is also important to take the weight of the tablet into account when selecting the compression force. The required level of stiffness is lower for a smaller tablet and a lower compression force is typically used. One skilled in the art would select an appropriate compression force in order to obtain the desired disintegration time for a specific sized tablet.

In one aspect, the dispersible tablets of this invention have a high porosity, showing rapid disintegration in an aqueous solution, such as water. The ability to rapidly disperse can be seen in standard tests. The disintegration time is preferably measured according to the standard test for dispersible tablets, described in European Pharmacopoeia 4.1, page 2435, (2002), in combination with European Pharmacopoeia 4, page 191, 2.9.1 (2002). This test examines the disintegration time of the tablets in water, at 15 to 25 ° C.

The dispersion can be observed visually. Disintegration is considered to have been obtained when no residue remains in the sieve or if there is residue, it consists of a soft mass without palpable firmness, non-wetted core or only fragments of coating (tablets) or only fragments of coating (capsules) remain on the sieve.

The tablets of the present invention preferably have a disintegration time of 3 minutes or less, when measured according to the above test. More preferably, the disintegration time is 2 minutes or less, even more preferably, the disintegration time is 90 seconds or less and, more preferably, the disintegration time is 30 to 65 seconds.

The stiffness or resistance to grinding of the tablets according to the present invention can be determined by standard tests. The tablet stiffness is preferably determined according to the standard test specified in European Pharmacopoeia 4, page 201, 2.9.8 (2002). A device such as a Kraemer® 3S tablet testing device can be used. This test determines the resistance to grinding the tablets, measured by the force necessary to disintegrate them by grinding.

The stiffness of the tablets of the present invention varies according to the weight and diameter of the tablets and the compressive strength. For a 200 to 300 mg tablet, for example, a 250 mg tablet, having a diameter of about 9 mm, the stiffness is preferably 3.57 to 8.16 kg strength (35 to 80 N). In order to obtain such stiffness, the compression force of 815.77 to 1121.69 kg force (8 to 11 kN) is preferably applied. For a 50 to 150 mg tablet, for example a 100 mg tablet, having a diameter of about 7 mm, the stiffness is preferably

2.55 kg force at 6.12 kg force (25 to 60 N) and can be obtained by applying a compression force of 713.8 kg force at 917.74 kg force (7 to 9 kN).

For other tablet weights and diameters, stiffness varies.

Thus, the advantageous properties of the present compositions can be demonstrated by the rigidity and time of disintegration of the tablets produced from such compositions. Consequently, in a preferred embodiment, the present invention relates to a pharmaceutical composition as defined above, where 250 mg of the composition, when pressed using a compression force of 815.77 to 1,121.69 kg force (8 to 11 kN) , with a diameter of 9 mm, and standard flat punches, forms a tablet having a stiffness of 3.57 to 8.16 kg strength (35 to 80 N). Preferably, the composition is pressed using a tablet press, such as the Fette® PT 2080 Rotary tablet press. Stiffness is measured by the standard procedure mentioned above, for example, using a Kraemer® 3S tablet testing device. The pharmaceutical composition is most preferably such that 250 mg of the composition, when pressed using a compression force of 968.73 kg force (9.5 kN), with a diameter of 9 mm, and standard flat punches, form a compressed having a stiffness of 4.08 kg force to 6.73 kg force (40 to 66 N). The disintegration time of a tablet formed in such a way from the composition is preferably 3 minutes or less, more preferably 90 seconds or less, when determined using the test specified above.

In an alternative embodiment, the present invention relates to a pharmaceutical composition as defined above, where 100 mg of the composition, when compressed using a compression force of 713.8 kg force to 917.74 kg force (7 to 9 kN) , with a diameter of 7 mm, and standard flat punches, form a tablet having a stiffness of

2.55 kg strength to 6.12 kg strength (25 to 60 N). More preferably, the pharmaceutical composition is such that, 100 mg of the composition, when pressed using a compression force of 846.36 kg force (8.3 kN) with a diameter of 7 mm, and standard flat punches, form a tablet having a stiffness of 2.96 kg force to 5.40 kg force (29 to 53 N). The disintegration time of a tablet formed in such a way from the composition is preferably as provided in the preceding paragraph.

The above statements of the invention define the pharmaceutical composition in terms of the properties of a specific tablet, which can be manufactured from such a composition. However, it is clear that the invention is in no way limited to tablets having such weight, diameter or stiffness, or only to a production process involving the use of such a compressive force. As discussed above, these values may vary for different types of tablets. The above definition is provided in order to clarify the advantageous intrinsic properties of the present pharmaceutical compositions, which means that when they are formulated in tablets, they provide a rapid disintegration time, in combination with a good degree of rigidity.

The tablets obtained by the compression process described above can vary in shape and be, for example, round, oval, oblong, cylindrical, flat or curved, or any other appropriate shape, and can also vary in size, depending on the concentration of therapeutic agents .

In a preferred embodiment of the invention, the tablets obtained by the compression process described above are round and flat. The edges of the tablets can be chamfered or rounded.

The compositions of this invention can be administered to a patient, such as a child, in the form of a rapidly disintegrating composition, for example, a dispersible tablet, the composition of which can be administered together with a liquid, for example, an aqueous medium, such as water. Upon adding the liquid to the formulation, for example, a unit dosage form or dosage, such as a tablet, for example, in a spoon, the composition quickly disintegrates to form a dispersion, for example, in less than 3 minutes, preferably less than 90 seconds, more preferably between 30 and 65 seconds, thus allowing for convenient administration. For administration to a child, a sweetener or other additive can be added to the aqueous medium, where the tablet is dispersed, in order to mask any unpleasant taste18

make the dispersion more pleasant.

When necessary, the compositions of the invention in the form of a rapidly disintegrating composition are preferably composed in unit dosage form, for example, as a dispersible tablet, capsule, granules or powder, preferably as a dispersible tablet. When the composition is in unit dosage form, each unit dosage form comprising rapamycin, or a derivative thereof, will suitably contain between 0.05 mg and 10 mg of the drug substance, more preferably between 0.1 and 5 mg; for example, 0.1 or 0.25 mg. Such tablets are suitable for administration 1 to 5 times daily, depending on the specific purpose of the therapy, the phase of therapy and the like.

Where the composition of this invention is in unit dosage form, for example, a dispersible tablet comprising an ascomycin, each unit dosage form will preferably contain between 1 mg and 50 mg of the drug substance, more preferably between 10 and 25 mg; for example, 10, 15, 20 or 25 mg. Such tablets are suitable for administration 1 to 5 times a day, depending on the specific purpose of the therapy, the phase of therapy and the like.

The compositions of the invention can show good stability characteristics, as indicated by standard stability experiments, for example, having a shelf life of up to one, two or three years and even longer.

The particles or granules obtained by any of the processes A to E, as described above, can be coated, for example, using an enteric coating. Suitable coatings can comprise cellulose phthalate, hydroxypropylmethylcellulose phthalate; a polymethacrylic acid polymer, for example, Eudragit® L, S; or hydroxypropylmethyl cellulose succinate.

The tablets obtained by the compression process described above can be additionally colored and the tablets marked, in order to provide an individual appearance and to make them readily recognizable. The use of dyes can serve to improve the appearance, as well as to identify the compositions. Dyes suitable for use in the pharmacy typically include carotinoids, iron oxides and chlorophyll. Preferably, the tablets of the invention are marked using a code.

The procedures that can be used are known in the art, for example, those described in L. Lachman et al. The Theory and Practice of Industrial Pharmacy, 3rd Ed, 1986, H. Sucker et al., Pharmazeutische Technologie, Thieme, 1991, Hagers Handbuch der pharmazeutischen Praxis, 4th Ed. (Springer Verlag, 1971) and Remingtoris Pharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970) or later editions.

The pharmaceutical compositions of the invention are useful for the same indications as the macrolide, for example, rapamycin or ascomycin. Pharmaceutical compositions of the invention comprising rapamycin or a rapamycin derivative are specifically useful for:

a) treatment or prevention of rejection of allo or cell, tissue or organ xenotransplantation, for example for combined heart, lung, heart-lung transplants, liver, kidneys, bladder, pancreas, insulin-producing cells, skin and corneas . Pharmaceutical compositions are also indicated for the prevention of graft-versus-host disease, as sometimes occurs after bone marrow transplantation;

b) treatment or prevention of autoimmune disease and inflammatory conditions, specifically inflammatory conditions with an etiology including an autoimmune component, such as, arthritis (e.g., rheumatoid arthritis, chronic progressive arthritis and deforming arthritis) and rheumatic diseases. Specific autoimmune diseases, for which the compounds of the invention can be used, include autoimmune haematological disorders (including, for example, hemolytic anemia, aplastic anemia, pure red blood cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma , Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic vomiting, inflammatory bladder disease auto20

immune (including ulcerative colitis and Crohn's disease), endocrine ophthalmology, Graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (type I diabetes mellitus), uveitis (anterior and posterior), sicca keratoconjunctivitis and vernal keratoconjunctivitis, fibrosis interstitial lung, psoriatic arthritis, glomerulonephritis (with and without nephrotic syndrome, for example, including idiopathic nephritic syndrome or minimally altered nephropathy) and juvenile dermatomyositis;

c) treatment or prevention of asthma;

d) treatment or prevention of chronic graft rejection or restenosis;

e) cancer treatment, hyperproliferative skin disorder, and the like;

f) treatment of infections, for example, fungal infections;

g) treatment or prevention of inflammation, especially in enhancing the action of steroids.

The pharmaceutical compositions of the invention, comprising ascomycin or an ascomycin derivative, are specifically useful, for example, in the treatment of hyperproliferative and inflammatory diseases of the skin and cutaneous manifestations of immune-mediated diseases.

More specifically, the compositions of this invention are useful as anti-inflammatories and as immunosuppressants and antiproliferative agents for use in the prevention and treatment of inflammatory conditions and conditions that require immunosuppression, such as:

a) prevention or treatment of:

- rejection of the transplanted organ or tissue, for example, heart, kidneys, liver, bone marrow and skin,

- graft-versus-host disease, such as after bone marrow grafts,

- autoimmune diseases, such as rheumatoid arthritis, systemic thematic lupus erythema, Hashimoto's thyroid, multiple sclerosis, myasthenia gravis, type I diabetes and uveitis,

- cutaneous manifestations of immunological mediated diseases21 • · · · · · ·· · ·· · · · · · · · · · · · ··· · · mind;

b) the treatment of inflammatory and hyperproliferative diseases of the skin, such as psoriasis, atopic dermatitis, contact dermatitis and additional eczematous dermatitis, seborrheic dermatitis, Liche planus, Pemphigus,

Bullous pemphigoid, bulky epidermolysis, urticaria, angioedemas, vasculitides, erythema, cutaneous eosinophilia, lupus erythematosus and acne; and

c) alopecia areata.

In a further aspect, the present invention provides for the use of a composition as defined above, for the manufacture of a medication for use as an immunosuppressant, for example, in the treatment or prevention of one of the diseases or disorders mentioned above.

Thus, in one aspect, the present invention provides a method of treating an individual suffering from a macrolide-treatable disorder, comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention, to an individual in need of such treatment. .

In another aspect, the present invention provides a process for administering a pharmaceutical composition of the invention to an individual in need of such therapy, which comprises (i) contacting the composition with water and (ii) ingesting the resulting dispersion.

The dispersible tablets of this invention can be dispersed before ingestion, for example, in 20 to 50 ml of water, with stirring.

The exact amount of the compositions to be administered depends on several factors, for example, the desired duration of treatment and the rate of release of the macrolide.

The compositions of the invention exhibit especially advantageous properties when administered orally; for example, in terms of consistency and level of bioavailability, obtained from standard bioavailability experiments. These experiments are carried out on animals, mice or dogs, or healthy volunteers.

Pharmacokinetic parameters, for example, levels of absorption and blood, also become surprisingly more predictable and pro22

administration problems with erratic absorption can be eliminated or reduced. In addition, the compositions are effective with tenside materials, for example, bile salts, being present in the gastrointestinal tract.

The utility of pharmaceutical compositions can be seen in standard clinical tests, for example, in known indications of active agent dosages, providing equivalent blood levels of active agent; for example, using dosages in the range of 0.01 mg to 5 mg / kg of body weight per day, for example, 0.5 to 5 mg / kg of body weight per day of rapamycin or a derivative thereof, in mammals, for example, children (for example, under 12 and, for example, at least 3 years old) or older, and in standard animal models; or, for example, using dosages in the range of 1 mg to 1,000 mg, for example, 2.5 to 1,000 mg, preferably 10 to 250 mg, per day, of an ascomycin, for an adult of 75 and in standard animal models. The increased bioavailability of the drug substance provided by the compositions can be seen in standard animal tests and clinical experiments.

The following is an exemplary description of the pharmaceutical composition of the invention.

Example 1

Preparation of a solid dispersion

A 2% solid dispersion (SD) composition is prepared, containing the following ingredients:

Weight (fl) Weight (%) 40-O- (2-hydroxyethyl) -rapamycin 0.04 2.0 Butylated hydroxytoluene 0.004 0.2 HPMC 3 cps 1.6 80.0 Lactose, monohydrate (200 mesh) 0.356 17.8 Total 2.0 100

The composition is prepared by (i) a mixture of 40-O- (2-hydroxyethyl) rapamycin and butylated hydroxytoluene (ii) dissolving the mixture obtained in (i) in an ethanol / acetone mixture, (iii) adding HPMC and lactose, (iv) homogeneous dispersion of the mixture obtained in step (iii) and (v) removal of solvents by evaporation. The resulting residue is dried, sieved and ground. Preparation of a pharmaceutical composition

A pharmaceutical composition (containing the solid dispersion 5 described above) is prepared containing the following ingredients (in parts by weight):

40-O- (2-hydroxyethyl) -rapamycin SD 2% 5

Crospovidone® 20

Aerosil® 3

Magnesium stearate 0.5

Lactose, anhydrous 71.5

Total 100

The composition is prepared by (i) a combination of solid dispersion (SD), lactose, Crospovidone® and Aerosil®, (ii) sieving (0.8 mm) and mixing, (iii) adding sieved magnesium stearate (0.8 mm) mm) and mixing. Preparation of a dispersible tablet

A dispersible tablet is obtained by pressing the mixture obtained in step (iii) into a tablet. 250 mg of the pharmaceutical composition is pressed with a Fette® PT 2080 Rotary tablet press, using a compression force of 1,070.7 kg force (10.5 kN) with a diameter of 9 mm and standard flat punches. The resulting tablet's stiffness is then assessed by measuring the force required to grind the tablet using a Kraemer 3S tablet tester. The rigidity of the tablets manufactured in accordance with these conditions was between

3.87 kg strength to 8.06 kg strength (35 and 79 N). The disintegration time of such tablets was 0.4 to 1.4 minutes (24 to 84 seconds).

Example 2

A pharmaceutical composition was prepared as described above. A dispersible tablet was prepared by pressing 100 mg of the pharmaceutical formulation with a Fette® PT 2080 tablet press

Rotary using a compression force of 764.79 kg (7.5 kN) with a diameter of 7 mm and standard flat punches. The stiffness of the tablets manufactured under these conditions was 2.55 kg strength to 8.06 kg strength (25 to 79 N). The disintegration time of such tablets was 1.1 to 1.7 minutes (66 to 102 seconds ).

The above examples illustrate compositions and tablets 5 useful for example in preventing transplant rejection or for the treatment of autoimmune disease, in the administration of 1 to 5 unit doses / day in a dose between 0.01 to 5 mg / kg body weight per day.

The examples are described with specific reference to 40-0- (2hydroxyethyl) -rapamycin. However, in the additional examples, the process described in examples 1 and 2 is repeated except that 40-O- (2-hydroxyethyl) rapamycin is replaced with an alternative macrolide. The alternative macrolide can be any rapamycin derivative or ascomycin derivative mentioned above, for example, FK-506 or 33-epi-chloro-33-deoxiascomycin. Tablets comprising such alternative macrolides have a stiffness and disintegration time that is similar to that provided above for tablets containing 40-O- (2-hydroxyethyl) -rapamycin and are also useful as immunosuppressants.

Claims (5)

1. Pharmaceutical composition, characterized by the fact that it is in the form of a dispersible tablet comprising a solid dispersion of 40-O- (2-hydroxyethyl) -rapamycin, a disintegrant comprising cross-linked polyvinylpyrrolidone and colloidal silicon dioxide, in which the composition comprises 1 to 5% colloidal silicon dioxide by weight, the solid dispersion of 40-O- (2-hydroxyethyl) -rapamycin comprising: (a) a medium vehicle comprising one or a mixture of water-soluble polymer selected from the group consisting of: hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinylpyrrolidone (PVP), poly (meth) acrylates, hydroxypropylcellulose (HPC) or a derivative thereof, a polyethylene glycol (PEG), a saturated polyglycosylated glyceride and a cyclodextrin; (b) a load selected from the group consisting of sucrose, lactose, amylose, dextrose, mannitol and inositol; (c) an antioxidant selected from the group consisting of butylated hydroxytoluene (BHT), butyl anisol hydroxy (BHA), DL-a-tocopherol, propyl gallate, ascorbyl palmitate and fumaric acid. 2. Pharmaceutical composition according to claim 1, characterized by the fact that 250 mg of the composition, when pressed using a force of 815.77 kg force to 1,121.69 kg force (8 to 11 kN) with a diameter of 9 mm and standard flat punches, form a tablet having a stiffness of 3.57 kg strength at 8.16 kg strength (35 to 80 N) and a disintegration time of 3 minutes or less. Composition according to claim 1 or 2, characterized by the fact that the tablet has a disintegration time of 90 seconds or less. 4. Use of a composition, as defined in any of claims 1 to 3, characterized in that it is for the manufacture of a medicament for use as an immunosuppressant. Process for producing a dispersible tablet containing 40-O- (2-hydroxyethyl) -rapamycin, as defined in any one of claims 1 to 3, characterized by the fact that it comprises: preparing a solid dispersion of 40-O- (2-hydroxyethyl) rapamycin, mixing the solid dispersion of 40-O- (2-hydroxyethyl) -rapamycin with a disintegrant comprising cross-linked polyvinylpyrrolidone and colloidal silicon dioxide, the composition being comprises 1 to 5% colloidal silicon dioxide by weight to form a pharmaceutical composition, and pressing the pharmaceutical composition to form the dispersible tablet.